Efficacy and safety of low-dose interleukin-2 in combination with methotrexate in patients with active rheumatoid arthritis: a randomized, double-blind, placebo-controlled phase 2 trial

Abstract

Rheumatoid arthritis (RA) is an aggressive autoimmune arthritis, and current therapies remain unsatisfactory due to low remission rate and substantially adverse effects. Low-dose interleukin-2 (Ld-IL2) is potentially a therapeutic approach to further improve the disease. This randomized, double-blind, placebo-controlled trial was undertaken to evaluate the efficacy and safety of Ld-IL2 in patients with active RA. Patients were randomly assigned (1:1) to receive Ld-IL2, defined as a dose of 1 million IU, or placebo in a 12-week trial with a 12-week follow-up. Three cycles of Ld-IL2 or placebo were administered subcutaneously every other day for 2 weeks (a total of 7 doses), followed by a 2-week break. All patients received a stable dose of methotrexate (MTX). The primary outcomes were the proportion of patients achieving the ACR20, DAS28-ESR <2.6, and the change from baseline in CDAI or SDAI at week 24. Secondary endpoints included other clinical responses and safety. The primary outcomes were achieved in the per-protocol population. The improvements from baseline in CDAI and SDAI were significantly greater across time points for the Ld-IL2 + MTX group (n = 17) than for the placebo+MTX group (n = 23) (P = 0.018 and P = 0.015, respectively). More patients achieved ACR20 response in the Ld-IL2 + MTX group than those in the placebo+MTX group at week 12 (70.6% vs 43.5%) and at week 24 (76.5% vs 56.5%) (P = 0.014). In addition, low Treg and high IL-21 were associated with good responses to Ld-IL2. Ld-IL-2 treatment was well-tolerated in this study. These results suggested that Ld-IL2 was effective and safe in RA. ClinicalTrials.gov number: NCT 02467504.

A chinese medicine formula (kunbixiao granule) for female rheumatoid arthritis: Study protocol for a double-blind, randomized, placebo-controlled trial

“…The DAS28-CRP is widely used as an indicator of RA disease activity and response to treatment, and clinical trials have used DAS28 to assess treatment effect ( Gardiner et al, 2005 ; Jain et al, 2021 ; Zhang et al, 2022 ). A change of ≥1.2 score is considered clinically significant difference ( Van Gestel et al, 1998 ).…”

“…Traditional Chinese Medicine (TCM) has shown advantages in the treatment of RA. Chinese medicine formula monotherapy or combined with Western medicine had better performance on improving clinical symptoms, preventing the disease progression, reducing serum rheumatoid factor and anti-cyclic citrullinated peptide antibodies, and improving the bone mineral density of RA than Western medicine monotherapy ( Cai, et al, 2018 ; Tang, et al, 2021 ; Zhang et al, 2022 ). But to date, there is no TCM clinical trial for RA in women.…”

Mechanisms regulating the loss of Tregs in HUPO mice that develop spontaneous inflammatory arthritis

“… 73 , 74 A phase 2 study suggests therapeutic benefit adding low dose IL-2 to methotrexate in patients with rheumatoid arthritis. 75 Modifications of IL-2 that prolong the half-life and enhance efficiency make this approach more achievable. 74 Our prior studies demonstrate that HUPO- Rag −/− arthritis is initiated in the absence of B or T lymphocytes but does not progress to severe disease, 27 suggesting that the reduction of Tregs is permissive, but is not responsible for the induction of disease.…”

CD4+T cell subset imbalances in rheumatoid arthritis

“…Our study shows large heterogeneity across patients with some with a predominantly Th1 profile, others a Th17 profile, or a Th1-like Th17 profile, while others are mainly characterised by a low IL-2 + Treg profile. As an example, stratifying patients by their IL-2 + Treg titres may dictate response to low-dose IL-2 therapy, as has now been successfully trialled in lupus [42] and RA [43]. Furthermore, a Japanese group found that stratified medicine for psoriatic arthritis patients increased response rates significantly [16].…”